Human cytomegalovirus (HCMV) is a β-herpesvirus and is also known as human herpesvirus-5 (HHV-5). Other species of cytomegalovirus (CMV) exist which infect additional mammals such as murine CMV (MCMV), guinea pig CMV (GPCMV), simian CMV (SCCMV), rhesus CMV (rhCMV) and chimpanzee CMV (CCMV). HCMV is a common herpesvirus that infects nearly 50% of the U.S. population. For the vast majority of human infected individuals, HCMV infection is asymptomatic. However, in conditions of illness, and immune suppression (e.g., HIV infection, drug-induced immune suppression in transplant patients) HCMV reactivation or primary infection causes a variety of clinical manifestations such as mononucleosis, hepatitis, retinitis, pneumonia, blindness and organ failure. In addition, in the setting of pregnancy, the acquisition of primary CMV infection, though of little consequence to the mother, can have severe clinical consequences in the developing fetus.
Congenital HCMV infection is of particular importance as many children born to mothers infected during pregnancy become infected in utero and suffer devastating clinical disease. In the United States and Europe, 126,000 women have primary HCMV infection during pregnancy and approximately 40,000 of the babies born to these mothers have congenital infection. In the U.S., 1 in 750 children are born with or develop disabilities due to HCMV infection, including: mental retardation, hearing loss, vision loss, organ defects, and growth defects. Congenital HCMV infection is the most common infectious cause of fetal abnormalities. After primary infection of a pregnant woman has occurred, there is currently no approved therapy for the prevention or treatment of fetal infection.
In 2005, Nigro and colleagues published a study in which human CMV hyperimmune globulin (HIG) was administered to expectant mothers with primary HCMV infection (Nigro et al. (2005) New Engl. J. Med. 353:1350-1362). In one arm of the study only 1 of the 31 infants born to HCMV-infected mothers were born with disease while 7/14 (50%) of children born to untreated women were born with HCMV disease. Id.
During pregnancy, HCMV can spread from the infected mother to the fetus via the placenta. The placenta, which anchors the fetus to the uterus, contains specialized epithelial cells, stromal fibroblast cells, endothelial cells, and specialized macrophages. The HCMV viral surface contains various viral glycoprotein complexes that have been shown to be required for infection of the specific cell types found in the placenta. A complex of CMV glycoproteins containing gH/gL and UL128, UL130 and UL131 (herein referred to as “Complex I”) is specifically required for infection of endothelial cells, epithelial cells and macrophages. A complex of CMV glycoproteins containing gH/gL and g0 (herein referred to as “Complex II”) is specifically required for infection of fibroblasts. HIG has been shown to block viral entry into all four of the placental cell types that are susceptible to HCMV infection.
Due to the difficulty of preparing and widely distributing HIG and the reluctance of physicians and the medical community to use human blood products, particularly in pregnant women, it would be most beneficial to create a composition comprising a monoclonal antibody or monoclonal antibodies that could protect fetuses from congenital HCMV infection. No monoclonal antibody composition to date has been developed for the prevention of maternal-fetal transmission of CMV. Lanzavecchia and Macagno have disclosed naturally-occurring antibodies that were isolated from the immortalized B cells of infected patients that bind to a conformational epitope resulting from the combination of UL130 and UL131 or a combination of UL128, UL130 and UL131 that neutralizes CMV transmission (U.S. Patent Publication Nos. 2008/0213265 and 2009/0081230). Shenk and Wang have disclosed antibodies that bind to proteins of Complex I (U.S. Pat. No. 7,704,510). Funaro et al. also disclose neutralizing antibodies to CMV in U.S. Patent Publication No. 2010-0040602. Additionally, an anti-gH monoclonal antibody, MSL-109 was tested in humans in two patient populations, allogenic bone marrow transplant recipients and patients with AIDS and CMV retinitis (Drobyski et al., Transplantation 51:1190-1196 (1991); Boeckh et al., Biol. Blood Marrow Transplant. 7:343-351 (2001); and Borucki et al., Antiviral Res. 64:103-111 (2004) without success.
U.S. application Ser. No. 13/248,998, incorporated by reference herein in its entirety, discloses humanized anti-HCMV monoclonal antibodies. Antibodies disclosed in U.S. application Ser. No. 13/248,998 were shown to have neutralizing potency comparable to human immunoglobulin from patients infected with HCVM (HIG) for inhibiting infection on fibroblasts, epithelial cells, endothelial cells and macrophages. These antibodies are useful, for example, for the prevention, inhibition and/or treatment of HCMV infection, congenital HCMV infection and infection of patients through HCMV-infected transplanted tissues.
There is a need in the art to detect therapeutic humanized monoclonal antibodies to HCMV in biological samples and/or clinical samples without also detecting other antibodies directed or not directed to HCMV (e.g., endogenous immunoglobulins). The invention provides anti-idiotypic antibodies that specifically detect certain anti-HCMV antibodies. These antibodies are useful, for example, in pharmacokinetic (PK) and pharmacodynamic studies and for the quantification and monitoring of therapeutic anti-HCMV antibodies in patients.